Apomorphine is prescribed in therapy for a number of indications. As a major indication, apomorphine may be used by injection or infusion to give benefit to patients with Parkinson's disease experiencing ‘wearing off’ or sudden and unpredictable ‘on/off’ fluctuations. Also apomorphine is prescribed to alleviate the dyskinesia and akinesia and it is also used effectively to treat sexual dysfunction. The terms ‘on/off’ or ‘motor fluctuations’ refer to when a patient finds he/she can no longer rely on the smooth symptom control that their drugs normally give them. Patients deriving the most benefit from apomorphine treatment are those with severe ‘off’ periods, but who are reasonably well when ‘on’.
Apomorphine can be administered in different ways: By a disposable pen to give intermittent injections or as an infusion via a syringe driver using a pre-filled syringe or as ampoules that are used with a continuous infusion pump.
Apomorphine can cause short-term nausea in the beginning of the treatment, and therefore an anti-nausea drug such as domperidone may be given for at least two weeks.
Many attempts have been made to make alternative non-parenteral apomorphine products, such as nasal sprays, nasal powder, and sublingual tablets. From the literature it is clear that attempts to develop a nasal product have failed so far, because of severe side effects in the nose in the form of vestibulitis, leading to a discontinuation of the treatment. Also a number of studies have reported that sublingual administration of apomorphine tablets is effective, but an unpredictable and sometimes long time to benefit may not offer any advantage as a rescue type of therapy. Comparison of 3 mg apomorphine subcutaneous injection and 30 mg apomorphine sublingual tablets in nine Parkinson's disease subjects in a blinded cross-over trial, found that the time to peak benefit was beyond 40 minutes with sublingual apomorphine, as compared with 21 minutes for the subcutaneous preparation. Chronic use of the sublingual formulation was associated with severe stomatitis in half the subjects. Other papers report that the occurrence of stomatitis of sublingual tablets at higher dosages may lead to cessation of treatment (Koller W and Stacy M, Neurology 2004;62:S22-S26).
To avoid the degradation (mainly oxidation) of apomorphine in a liquid composition attempts have been made to separate the apomorphine active agent in one compartment from a second compartment containing a carrier for the drug substance. A recent patent application (US 2009/0023766) describes a study using a two compartment kit consisting of an apomorphine powder compartment and a solvent compartment which are combined just before being squirted onto a volunteer's tongue. The study results are similar to those described in WO 97/06786, which discloses oral fast-dissolving compositions for dopamine agonists, and in WO 99/66916, which describes slow release apomorphine-containing dosage forms for ameliorating male erectile dysfunction. In another recent application (US 2011/0111011) a great variety of sublingual apomorphine containing gels, lozenges, pills, tablets, films or strips are described.
For nasal delivery of apomorphine mainly aqueous solutions of apomorphine have been described in the literature. The aqueous solubility of apomorphine is only about 10 mg/ml (1% w/w). This means that with the usual nasal spray volume of 0.1 ml per nostril, the maximum achievable dose per nostril is too low, about 1 mg apomorphine. Also apomorphine in aqueous nasal sprays is extremely susceptible to oxidation and therefore attempts to develop nasal sprays containing a lot of water have failed so far. An additional problem is nasal irritation and vestibulitis which is most probably caused by the oxidation products of apomorphine.
In WO2005/041966 more concentrated aqueous solutions of apomorphine as dibenzoylester are described for intranasal administration, comprising apomorphine 3.5% w/w. These solutions contain a lot of water in addition to propylene glycol as solvent up to a concentration of 40% (w/w). WO00/76509 discloses a variety of aqueous and non-aqueous apomorphine nasal compositions which may comprise a range of different solvents. Propylene glycol is mentioned as an effective solvent in vitro, however WO00/76509 does not report any in vivo testing of nasal compositions comprising propylene glycol and fails to reveal that propylene glycol in concentrations above 50% is extremely damaging for the nasal mucosa.
WO2005/067893 teaches that propylene glycol, glycerol, polyethylene glycol and povidone are attractive solubilizers for use in nasal products, because in low concentrations they do not have a strong adverse effect on ciliary movement in the nose. Disclosed are in vitro experiments, according to a previously published method (Merkus et al, 2001), describing the effect of four different solubilizers [25% propylene glycol, 15% glycerol, 25% polyethylene glycol 400 and 5% povidone], dissolved in a Locke-Ringer solution, on the ciliary beat frequency (CBF) of ciliated tissue. All four solvents show a strong decrease in CBF after 15 minutes. However, after rinsing with a pure Locke-Ringer solution, the effects on CBF appeared to be completely reversed within 20 minutes.
However, further experiments which have now been carried out using the abovementioned method show that propylene glycol in concentrations of 50% (v/v) are extremely ciliotoxic. The results of these experiments are illustrated in FIGS. 1, 2 and 3, from which it will be seen that after 5-15 minutes contact with 50% propylene glycol all cilia activity is completely arrested. No ciliary beat frequency could be measured any more. Furthermore, rinsing with a Locke-Ringer (LR) solution after 15 minutes did not result in an activation of the ciliated cells. Obviously the ciliated cells have been irreversibly damaged by the extreme hyperosmolar concentration of 50% propylene glycol. The effects of 10% and 25% propylene glycol are reversible, whilst the effect of 50% is not reversible, as demonstrated in FIGS. 1, 2 and 3. Thus, a nasal formulation containing a drug like apomorphine, dissolved in 50% or more (v/v) propylene glycol, is not a viable option, because it has to be administered in Parkinson's disease on a regular basis, for instance daily or several times per day or per week. On the other hand, such a high concentration of propylene glycol is needed to solubilise sufficient apomorphine (several mg per 0.1 ml) to treat a patient with off-periods in Parkinson's disease.
There is a strong medical need for a stable apomorphine formulation which is specifically formulated for treating off-periods in Parkinson's disease, without having the abovementioned disadvantages and problems.
It is an aim of the present invention to provide such a formulation. The formulation of the present invention contains at least about 50% propylene glycol to solubilise a sufficient amount of apomorphine in a small volume to allow adequate doses of apomorphine to be comfortably administered via the buccal and gingival route. A small volume is necessary because otherwise the administered solution is swallowed immediately and apomorphine is not active because it is metabolized in the gastrointestinal tract.
The buccal and gingival mucosa does not contain ciliated cells and has a much more robust structure than the nasal mucosal tissues. The buccal mucosa contains about 40 cell layers while in contrast the nasal ciliated epithelial cells consist of only one cell layer. Also, a nasal puff of 0.1 ml, containing 50% or more propylene glycol, is not only detrimental for the nasal ciliated mucosa, but also extremely irritating in the nose, while such a spray on the buccal mucosa is not irritating, in fact the taste of propylene glycol in the mouth is sweet.
As a consequence, a high concentration of propylene glycol (50% and more) can be used safely on the buccal mucosa, making it possible to solubilise and administer a sufficient amount of apomorphine. The present invention compositions provide a buccal/gingival pharmaceutical formulation of apomorphine causing as little irritation in the mouth as possible and having as high a bioavailability as possible and in a small volume, which is not swallowed easily. This present invention further offers a therapy to treat off periods in Parkinson's patients by providing an apomorphine buccal/gingival solution in the range of for instance 25-100 μl, containing at least 50% (v/v) of propylene glycol as solvent and comprising up to about 8 mg of apomorphine per 100 μl.